Abstract:

Introduction: Biomarkers of brain Aβ amyloid deposition, measured either by CSF or PIB PET imaging, are
significant predictors of future progression from MCI to AD, as are MRI measures of brain atrophy. Our objective
was to compare these two classes of biomarkers to predict time to progression and evaluate their effect on the
hazard of progressing.

Methods: A total of 218 MCI subjects were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
The primary outcome was time to conversion from a diagnosis of MCI to AD. Hippocampal volume was measured
from FreeSurfer and adjusted for total intracranial volume. We used a new method of converting CSF Aβ42 into
PIB PET units and combining CSF and PIB PET imaging data to produce equivalent measures of “brain Aβ amyloid
load” from either biomarker source.

Results: Over a median progression-free follow-up time of 1.7 years, 86 subjects progressed from MCI to AD.
The overall hazard ratio [(HR); 95% CI] for progression based on comparing the upper vs the lower quartiles
was 2.5 (1.4 to 4.3) for Aβ amyloid load and 2.6 (1.9 to 3.6) for comparing the lower to the upper quartile for
hippocampal volume. The relationship between hazard of progressing and increasingly abnormal hippocampal
volume (functional form) was linear. In contrast, there was evidence of non-linearity for Aβ amyloid load in the
form of a plateau in terms of risk. MRI and Aβ amyloid load remained significant in models that included both
biomarkers as predictors.

Conclusions: Biomarkers of neurodegeneration (i.e. atrophy on MRI) and brain Aβ amyloid deposition predict
conversion from MCI to AD independently and also provide complimentary predictive information. However, the
functional form of these two classes of biomarkers differs such that at some point additional amyloid load does
not confer additional risk.